It is well known that in evaluating a drug's merit, considerations of onset (bioavailability) and adverse side effects are inseparable from the drug's efficacy. Each is an important part of the drug's overall therapeutical profile. An early onset is important. It brings the relief quickly and therefore promotes patient compliance.
Sulindac is a non-steroidal antiinflammatory and analgesic drug (NSAID) known since the early 1970's. It is claimed in U.S. Pat. No. 3,654,349 issued to T. Y. Shen et al. in April 1972, and commercialized by Merck & Co., Inc. under the tradename CLINORIL. However, sulindac has a slow onset of activity which is due to its poor solubility in an acidic environment such as the stomach.
Sulindac is insoluble in water below pH 4.5, but its sodium salt is very soluble. It was thought that sodium sulindac, like sodium salts of other NSAIDs, for example, indomethacin, should have a much better bioavailability and a much shorter onset of activity than the parent compound, sulindac itself. Surprisingly, no appreciable difference in onsets was found between sulindac tablets and the aqueous solution of sodium sulindac in spite of numerous experiments. Based on historical data in man, sodium sulindac given as an oral solution exhibited no improved onset of activity when compared to sulindac given as a tablet, 10 mg/ml or 40 mg/ml oral suspension, a rectal suppository, an intramuscular injection suspension or even as its active metabolite (sulindac sulfide).
Tromethamine or sodium salts of indomethacin, naproxen and aspirin are known (British Pat. No. 2,059,768; and German Pat. No. 134,672). These salts all showed enhanced bioavailability of the drug. Thus, it was totally unexpected that no such conventional improvement of bioavailability or onset of activity was observed for the sodium sulindac and sulindac tromethamine salt when they were tested by themselves.
Although sodium sulindac, sodium bicarbonate and tromethamine are known, there is no known combination of these salts.
However, when a sufficient amount of a base such as tromethamine and/or sodium bicarbonate is combined with sodium sulindac, an unexpected improvement of bioavailability and an earlier onset of activity resulted.
It is therefore the object of this invention to provide a novel combination of sodium sulindac and a base with an improved onset, shorter time to peak activity and enhanced bioavailability than sodium sulindac alone.
It is also the object of this invention to provide a pharmaceutical composition of the combination for the treatment of inflammation and pain.
Finally, it is the object of this invention to develop a method of treatment comprising the administration of the novel combination to patients suffering inflammation and pain.